Kinetic Modeling of API Oxidation: (1) The AIBN/H₂O/CH₃OH Radical "Soup".

Area of Science:

• Chemical kinetics
• Pharmaceutical analysis
• Computational chemistry

Background:

• Active pharmaceutical ingredient (API) stress testing is vital for assessing chemical stability and identifying degradation products.
• Detailed kinetics and reactive species, particularly reactive oxygen species, in API stress testing systems remain largely uncharacterized.
• Understanding API oxidation mechanisms is essential for accurate stability predictions.

Purpose of the Study:

• To develop a detailed chemical kinetics model for a representative API stress testing system.
• To identify and quantify prominent reactive species, including reactive oxygen species, under varied conditions.
• To establish a foundation for quantitative kinetic studies of API oxidation.

Main Methods:

• Application of *ab initio* electronic structure calculations for automated kinetic model generation and refinement.
• Investigation of an azobis(isobutyronitrile) (AIBN)/water/methanol stress-testing system.
• System parameters included varied cosolvent ratios (50%/50% to 99.5%/0.5% vol water/methanol), 5.0 mM AIBN, pH 4-10, and 40 °C.

Main Results:

• At acidic conditions, hydroxymethyl alkoxyl is the dominant alkoxyl radical.
• At basic conditions, cyanoisopropyl alkoxyl becomes the dominant alkoxyl radical, though at lower concentrations.
• Superoxide is the prominent radical at neutral and basic pH, while peroxyl radicals are significant at acidic pH.

Conclusions:

• The study identifies key reactive species in a model API stress testing system across different cosolvent and pH conditions.
• The findings provide a basis for in-depth quantitative kinetic studies of API oxidation.
• Novel software tools for automated chemical kinetic model generation and *ab initio* refinement were demonstrated.